Three Part Question

In [an adult presenting with peripheral anthracycline extravasation] will [treatment with intravenous dexrazoxane] [reduce the risk of soft tissue necrosis]?

Clinical Scenario

A 28 year old man with Hodgkin’s lymphoma presents to the Emergency Department with increasing pain, swelling and erythema of the forearm following intravenous administration of doxorubicin a few hours ago at your local specialist cancer treatment centre. The pain was described as severe and constant with localised swelling, erythema, warmth and limited movement of the wrist. You suspect extravasation of anthracycline from the cannula site and as you initiate local measures of limb elevation and cooling, you wonder if emergency intravenous administration of dexrazoxane may be beneficial in reducing the risk of soft tissue necrosis and subsequent debridement.

Patients assessed for efficacy had treatment within 6 hours of extravasation of the anthracycline (confirmed by fluorescence biopsy) with intravenous infusion of dexrazoxane for 1-2 hours daily three consecutive days given in the opposite arm. The first and second doses were 1000mg/m2 and the third dose was 500mg/m2 up to a maximal total dose of 2000, 2000 and 1000mg, respectively..

Patients assessed for safety occurred due to negative or absent biopsies, treatment commencement >6hrs after extravasation, self-exclusion during treatment or inadequate clinical data..

Patient assessed at 24hrs, 48hrs, weekly for the following month and on day 90..

TT01 – 18 patients assessed for efficacy and 23 for safety TT02 - 36 patients assessed for efficacy and 57 for safety Primary: TT01: 18/18 patients did not develop surgery-requiring necrosis (100%) TT02: 35/36 patients did not develop surgery-requiring necrosis (97.4%) Secondary: Treatment delay TT01- 6/18 patients had treatment delay (33%) TT02 -10/36 patients had treatment delay (27.8%) Toxicity: Combined total of 76 CTC Grade 1-3 clinical adverse events occurred, most common being mild pain in 10 patients (19%) and mild sensory disturbances in 9 patients (17%). No CTC grade 4 clinical adverse events or treatment-related deaths occurred. Combined total of 226 CTC Grade 2-4 laboratory based toxicity occurred, most commonly due to suppression of bone marrow function as would occur with chemotherapy, with one third of patients having mild and reversible elevation of liver enzymes. There was no indication that subsequent chemotherapy in such patients was more toxic (no data provided).

Multicentre non-randomised single arm studies with no control group for comparison. The working assumption was that biopsy-positive anthracycline extravasation had 100% rate for surgery, and suspected but not biopsy-verified anthracycline extravasation had 35-50% rate for surgery, based on previous published data. .

2 out of 80 enrolled patients excluded but were still included in results analyses. .

Procedure for clinical evaluation and data review were vague in description thus suggesting difficultly in standardizing reporting of findings and results risking considerable subjectivity for the clinical adverse events..

No moderate-term data provided despite reputed 90 day follow up..

Comment(s)

The advice for the intravenous systemic use of dexrazoxane, which appears to function as a reversible topoisomerase II inhibitor and iron chelator (Jordan et al), in anthracycline (daunorubicin, doxorubicin, epirubicin and idarubicin) extravasation injury was built on data from animal models, case reports and small uncontrolled case studies (Mouridsen et al; Langer et al; Conde-Estévez et al) and had been approved by both the European Agency for the Evaluation of Medicinal Products and the US Food and Drug Administration from 2007 following the publication of the study by Mouridsen et al. Reported side effects included mild local pain and sensory disturbance, transient disturbance of liver function test and bone marrow suppression, nausea, vomiting, diarrhoea and somtatitis. Other case reports or case series were not included in the Best BET analysis as they were deemed to be of weaker level of evidence with a risk of publication bias.

Extravasation of the newer liposomal anthracycline preparations is generally not associated with necrotic injury (Curtit et al). However, for the patient who develops symptomatic extravasation of liposomal doxorubicin, dexrazoxane may still be beneficial (Vos et al).

Nonetheless, local general measures such as immediate cessation of the infusion, elevation of the affected limb, use of intermittent cold compress and leaving in-situ of the cannula for attempted aspiration of the fluid from the extravasated site is generally still recommended as additional supportive measures even though firm clinical evidence for such is lacking.

Editor Comment

CTC, common toxicity criteria (version 2.0).

Clinical Bottom Line

There is promising clinical evidence for the safe emergency use of intravenous dexrazoxane within 6 h of peripheral extravasation of anthracyclines to minimise the risks of tissue damage, need for surgical debridement and chemotherapy treatment delay when compared with other non-pharmacological and pharmacological treatments.